Drugs and the Genome - NO L.O.s

Question 1

Give some examples of types of variants/mutations. (3)

Answer 1

Single nucleotide variants
Insertions and deletions
Copy Number Variants

Question 2

What is GWAS?

Answer 2

Large-scale genotyping (genome-wide association study)

Question 3

What is the pattern of inheritance of familial hypercholesterolaemia?

Answer 3

Autosomal dominant

Question 4

What does familial hypercholesterolaemia cause?

Answer 4

Premature CHD 30-40yrs
5% MI under 50 yrs
Arcus, Xanthalasma, Tendon Xanthomata

Question 5

What causes the effects of familial hypercholesterolaemia?

Answer 5

Mutations in LDL receptor - gain of function mutation in PCSK9. This causes LDL receptors bound to PCSK9 to be digested in the lysosome, instead of the receptor being recycled.

Question 6

How common is familial hypercholesterolaemia?

Answer 6

1 in 250

Question 7

What three monoclonal antibodies inhibit PCSK9 to treat hyperlipidaemia?
Are they effective?

Answer 7

Evolocumab, alirocumab and bococizumab

Injectable & safe with 41% to 58% reduction in cholesterol

Question 8

What is the average life expectancy in cystic fibrosis?

Answer 8

37.4 years old

Question 9

How many people are carriers of CF?

Which population is it more common in?

Answer 9

1 in 25

White Europeans

Question 10

What is the combination therapy for CF?

Who is suitable?

Answer 10

Combination of ivacaftor and lumacaftor

Ages 12 and older with the ∆F508 mutation

Question 11

How do ivacaftor and lumacaftor work?

Answer 11

Improve lung function, prevent channel degradation, improve channel function

IVACAFTOR - augments CFTR channel opening
LUMACAFTOR - facilitates ∆F508 mutant protein folding, lowers sweat chloride concentration

Question 12

Which gene is affected in CF?

Answer 12

CFTR

Question 13

What is TALEN?

Answer 13

DNA-cutting enzyme - deactivates immune genes to avoid rejection and protect the new cells from anti-cancer drugs that the patient is taking.

Question 14

What is the Thiopurine Methyl Transferase (TPMT) test?

Answer 14

A phenotypic test - TPMT metabolises azathioprine and
6-mercaptopurine. Thioguanine accumulation inversely related to TPMT activity. Associated with severe haemopoietic toxicity.

Question 15

What do VKORC1 polymorphisms affect?

Answer 15

30% of the dose variation - less susceptible to suppression by warfarin, e.g. African Americans.

Question 16

Group A VKORC1 polymorphisms - what does this cause?

Answer 16

more rapid achievement of a therapeutic INR

Question 17

CYP2C9 polymorphisms explain 10% of the dose variation of warfarin, mostly in Europeans. How does this differ from VKORC1?

Answer 17

CYP2C9 polymorphisms do not influence time to effective INR as opposed to VKORC1, but they do shorten the time INR >4.

Question 18

Abacavir can cause a skin hypersensitivity reaction. How can this be tested for?

Answer 18

HLA-B*5701

Question 19

Trastuzumab (Herceptin) - what is this?

Answer 19

Herceptin targets the HER2 protein, present on cell surfaces. Overproduction of HER2 causes the uncontrollable cell growth.

Question 20

What is the HercepTest?

What two cancers is it used for?

Answer 20

Identifies breast cancers with HER2 overproduction and predicts response to Herceptin.
Also used in gastric cancer.

Question 21

What targeted therapy can be used for melanoma?

Answer 21

BRAF inhibitors

Question 22

What mutation does Gefitinib target? Which cancer?

Answer 22

Lung cancer - epidermal growth factor mutation